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Basic Science and Translational Research

(P 27) MOLECULAR CHARACTERIZATION OF RESPONSE TO NEOADJUVANT CHEMORADIATION IN PATIENTS WITH LOCALLY ADVANCED SOFT TISSUE SARCOMAS

    Author(s)

  • Klaudia Bobak, MSc

    PhD student
    Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology
    Warsaw, Mazowieckie, Poland

    • Co-Author(s)

  • JP

    Jakub Piatkowski, PhD

    Researcher
    Institute of Genetics and Biology, Faculty of Biology, University of Warsaw
    Warszawa, Mazowieckie, Poland

  • PG

    Paweł Golik, Prof.

    Institute of Genetics and Biotechnology, Faculty of Biology, University of Warsaw
    Warsaw, Mazowieckie, Poland

  • AT

    Andrzej Tysarowski, PhD

    Cancer Molecular and Genetic Diagnostics Laboratory, Maria Sklodowska-Curie National Research Institute of Oncology
    Warsaw, Mazowieckie, Poland

  • KS

    Katarzyna A. Seliga, PhD

    Cancer Molecular and Genetic Diagnostics Laboratory, Maria Sklodowska-Curie National Research Institute of Oncology
    Warsaw, Mazowieckie, Poland

  • Mateusz J. Spalek, MD, PhD (he/him/his)

    Associate Professor Deputy Head of Radiotherapy I Department
    Maria Sklodowska-Curie National Research Institute of Oncology
    Warszawa, Mazowieckie, Poland

  • AS

    Anna Szumera-Cieckiewicz, MD, PhD

    Maria Sklodowska-Curie National Research Institute of Oncology
    Warsaw, Mazowieckie, Poland

  • MW

    Michal Wagrodzki, MD, PhD

    Maria Sklodowska-Curie National Research Institute of Oncology,
    Warsaw, Mazowieckie, Poland

  • HK

    Hanna Kosela-Paterczyk, MD, PhD

    Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology
    Warsaw, Mazowieckie, Poland

  • Piotr Rutkowski, MD, PhD

    Head of Department of Soft Tissue/Bone Sarcoma and Melanoma
    Maria Sklodowska-Curie National Research Institute of Oncology
    Warsaw, Mazowieckie, Poland

  • AC

    Anna Malgorzata Czarnecka, prof. dr hab. n. med.

    prof. dr hab. n. med.
    Maria Sklodowska-Curie National Research Institute of Oncology
    Warsaw, Mazowieckie, Poland

Objective: Soft tissue sarcomas (STS) are a heterogeneous and complex group of neoplasms. STS remain a diagnostic and treatment challenge. A multidisciplinary approach to any single case is mandatory to define a tailored therapeutic plan through case-specific evaluation and to decide which treatments should be applied. This study aimed to identify the molecular profile of STS to find new and more efficient therapeutic approaches.

Methods: We analysed core biopsy samples of 29 patients before treatment. Patients were treated preoperatively with 5×5 Gy radiotherapy combined with 3 cycles of doxorubicin-ifosfamide chemotherapy. For Next-Generation Sequencing, the TruSight Oncology 500 kit (Illumina) and FusionPlex Sarcoma v2 (ArcherTM) were used. The Genome Analysis Toolkit (GATK) package, Arriba, PureCN, and OpenCRAVAT software were used to analyze sequencing data. The response to neoadjuvant therapy was assessed using the European Organization for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group (EORTC-STBSG) recommendations.

Results: The most common gene fusions consist of genes related to cell proliferation – MAPK or PI3K-AKT-mTOR pathways (e.g., FGFR1, PIK3CA, ROS1, JAK2, AKT3) and genes related to the apoptosis pathway (FOXO1, BCL2, TP53, HGMA2). Additionally, three patients with detected ROS1-associated gene fusions showed a good pathological response to treatment.
The most frequent amplification, with the highest level of amplification, was the MDM2 gene, found in 13.8% of patients with a poor pathological response to treatment. Amplifications of the FGF7 and RICTOR genes were detected in over 10% of cases. The most frequent deletion was loss of the PTEN gene, detected in four cases (in one case, loss of two copies of the gene).
The most pathogenic point mutations were detected: three in the TP53 gene (c.733G>A, c.817C>T, c.814G>A), and one in the MET gene (c.2975C>T). Each of the patients with STS with these molecular alterations progressed to distant metastases and/or death.

Conclusion: Cell cycle, apoptosis and proliferation pathways are deregulated in STS. Some of the molecular changes involve the same genes, suggesting a possible link with the development of STS. The obtained results may indicate new therapeutic targets in the treatment of STS.